Management of the patient with Lymph Node Involvement Michael A Henderson Peter MacCallum Cancer Center Univ of Melbourne
Lymph Node Field Recurrence Most important prognostic factor for early stage melanoma 80% of all first recurrences 10-15% of T1 melanomas - LNF relapse 20-50% of T2 -T4 melanomas - LNF relapse (but reduced by SNB) Previously LNF relapse occurred mainly in pts with thicker lesions 10-15% of all LNF relapses occur in patients with no identifiable primary lesion 25% of patients with a LNF relapse will develop a further relapse Lymphadenectomy is a morbid procedure Overall survival is approximately 40% 5 yrs
Quality Assurance in Surgery Metrics for surgery quality are notoriously elusive Little ROBUST data relating adequacy / quality of surgery to outcomes Commonly Accepted that adequate surgery is necessary Ann Surg 1983 Balch -identified inadequate surgery in 20 of 136 pts in an adjuvant study -higher rates of regional recurrence and poorer survival
Lymph Node Ratio Quantification of tumor burden - Ratio of involved nodes to resected nodes Probably provides superior prognostic information to the standard AJCC lymph node definitions Permits an assessment of the extent, adequacy or completeness of surgery which depends on a derived / agreed / arbitrary minimum node count for the major lymph node basins Strong evidence that adequate LNR is associated with better regional control, improved survival (pt was more likely to be treated in a major center)
Melanoma Care -Performance Evaluation Measure 4 Inguinal Lymphadenectomy at least 5 lymph nodes resected Measure 5 Axillary Lymphadenectomy at least 10 lymph nodes resected Minami CA Ann Surg Onc 2016
Late Surgical Morbidity maximum Grade 2 4 (ART v OBS) Subcutaneous Tissue Fibrosis 49% v 27% * p = 0.042 H + N Axilla Groin 60% v 34% * p = 0.045 60% v 34% * p = 0.045 Chronic Pain 24% v 17% 23% v 31% 23% v 31% Nerve Damage 19% v 15% 26% v 19% 26% v 19% Joint Discomfort (RT field) 21% v 12% 13% v 13% 13% v 13% Other Morbidity 21% v 20% 39% v 29% 39 % v 39%
Regional Relapse following Lymphadenectomy 5 yr Regional Failure % 5 yr Survival % Low Risk 1-2 pos nodes microscopic ECE 5-10% 50% Intermediate Risk High Risk 3-5 pos nodes max node size 30-60mm ECE >5 pos nodes Matted nodes Max node size >60mm close margins 25-30% 30% 50% 15%
Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3,. randomised controlled trial Michael A Henderson, Bryan H Burmeister, Jill Ainslie, Richard Fisher, Juliana Di Iulio, B Mark Smithers, Angela Hong, Kerwin Shannon, Richard A Scolyer, Scott Carruthers, Brendon J Coventry, Scott Babington, Joao Duprat, Harald J Hoekstra, John F Thompson 2015;16:1049-60 Trans-Tasman Radiation Oncology Group
Main Eligibility Criteria OR OR First, Isolated, palpable, single LNF recurrence no previous local, in transit or distant recurrence Standard Surgical Procedure Minimum lymph node numbers harvested (protocol) High Risk of further LNF Recurrence No of Positive Lymph Nodes Parotid 1 Neck >1 Axilla >2 Groin >3 Maximum Positive Lymph Node Size Parotid, Neck + Axilla Groin Extra Nodal Spread 30 + mm 40 + mm
Trial Schema Surgery for Lymph Node Field Recurrent Melanoma Main Eligibility Criteria Completely resected, palpable, nodal metastatic melanoma No previous or concurrent local, in transit or distant metastatic relapse At significant risk of lymph node field relapse Stratification (minimization) 1. Institution 2. Lymph node field site (3 levels) 3. Number of positive nodes (2 levels) 4. Metastatic node diameter (2 levels) 5. Extent of extra-nodal spread (3 levels) RANDOMISATION Adjuvant Radiotherapy n = 109 48 Gy 20 fractions Observation n = 108 (delayed Surgery + RT for relapse)
ANZMTG 01.02 / TROG 02.01 Radiotherapy reduced the risk of LNF relapse by 50% but had no impact on survival % LNF relapse-free 100 90 80 70 60 50 40 30 ART OBS HR(ART:OBS) = 0.52, P = 0.023 % surviving 100 90 80 70 60 50 40 30 OBS ART HR(ART:OBS) = 1.27, P = 0.21 20 10.25.5 1 2 4 Hazard ratio 95% CI 20 10.25.5 1 2 4 Hazard ratio 95% CI 0 1 2 3 4 5 6 7 8 9 10 Years from randomisation 0 1 2 3 4 5 6 7 8 9 10 Years from randomisation Time to LNF relapse by arm (First relapse; n = 217) Overall survival by arm (Eligible patients; n = 217) 11
ANZMTG 01.02 / TROG 02.01 Radiotherapy increased lower limb volumes Mean + 2SE 7.3% difference P = 0.014 * Leg volume ratio = volume of affected leg / volume of other leg
Late Radiotherapy Toxicity Toxicities recorded: Skin, RT pain, subcutaneous tissue, bone, joint, nerve damage, inner ear, middle ear, other, (brain,spinal cord,mucous membrane, small bowel, lung) Late RT Toxicities, RTOG/EORTC Late Radiation Morbidity Scoring Scheme ART arm Grade 2-4 toxicity >30% Head + Neck (n = 27) Axilla (n = 29) Groin (n = 34) Skin Nerve Skin Subcutaneous Skin Subcutaneous Other 37% 37% 44% 41% 46% 67% 38% Presented by: Michael A Henderson
ANZMTG 01.02 / TROG 02.01 FACT-G QOL -No Difference Regional Symptoms Questionnaire -RT worse Adverse Events RT group more pain and subcut fibrosis Better QoL FACT-G Worse symptoms RSQ WorseQoL P = 0.80 Better symptoms P=0.035 Trans-Tasman Radiation Oncology Group 14
Overall Survival from First LNF Relapse 17 (of 26) OBS pts eligible* for salvage surgery + RT % surviving 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 Years from salvage RT * First diagnosis of isolated LNF relapse, amenable to resection, registered for salvage RT Presented by: Michael A Henderson Median survival: 27 months 95% CI 35%
Conclusions Adjuvant RT reduced the risk of LNF recurrence by 48% (95% CI = 0.31 to 0.88, p= 0.023) There were no discernable differences in either relapse-free survival or overall survival between the 2 treatment groups Overall Survival was approximately 40% at 5 yrs Overall Survival after lymphadenectomy was related to the presence of extra-nodal extension, increasing number of positive lymph nodes and male sex (multivariable analysis)
Conclusions (2) The presence and extent of extra-nodal spread and non-use of RT were predictive of an increased risk of further LNF relapse Surgical Toxicity: Subcutaneous tissue fibrosis which was worse in the ART arm (HR = 2.25 p < 0.001) was an ongoing and worsening problem Late RT toxicity was common (>30%), mainly due to effects of RT on skin and subcutaneous tissue (higher in the lower limb). Grade 3/4 toxicity was not uncommon
Conclusions (3) Lymphoedema occurred in both arms, upper limb volumes -no difference lower limb volumes higher in Adjuvant RT arm (7.3% p = 0.014) There were no differences in Quality of Life as assessed by the FACT-G tool Regional Symptoms were worse in the Adjuvant RT arm (p = 0.035)
Unresolved Surgical Issues Extent of Surgery Inguinal v inguinal + pelvic lymphadenectomy Type and extent of cervical lymphadenectomy Minimising / Managing surgical morbidity Lymphoedema is a major issue Minimal access techniques
Long Term Prospective Assessment of Quality of Life and Lymphedema after Inguinal or Inguinal and Pelvic Lymphadenectomy for Recurrent Melanoma in the Groin MA Henderson, R Fisher, J Di Iulio, D Gyorki, J Spillane, D Speakman, B Burmeister, J Ainslie, M Smithers, A Hong, K Shannon, R Scolyer, S Carruthers, B Coventry, S Babington, J Duprat, H Hoekstra, JF Thompson Trans-Tasman Radiation Oncology Group SSO March 2016
Lymphoedema Limb Volume Ratios by operation Trans-Tasman Radiation Oncology Group 21
Adverse Events -Surgical (CTC-AE v2) Skin, pain, joint discomfort, subcutaneous tissue fibrosis, nerve damage, other 35 of 69 pts (52%) had a Grade 2-4 AE 2 pts had Grade 4 AEs (1 RT 1 Obs) Pain p=0.08 Joint p=0.015 Grade 0 1 2 3 Inguinal 6 21 12 2 Ing + Pelvic 12 7 3 0 Grade 0 1 2 Inguinal 15 18 8 Ing + Pelvic 14 8 0 Trans-Tasman Radiation Oncology Group 22
FACT-G QOL (Global Score) by Operation Trans-Tasman Radiation Oncology Group 23
Regional Symptomatology Score (Global) by Operation Trans-Tasman Radiation Oncology Group 24
Lymph Node Field Relapse by Operation Trans-Tasman Radiation Oncology Group 25
Overall Survival by Operation Trans-Tasman Radiation Oncology Group 26
Adjuvant Systemic Therapy Interferon Mocellin meta-analysis DFS HR.82, OS HR.91 Ipilimumab 2016 Targetted therapies / PD-1 to come Optimal Sequencing and timimg / Case selection / role for cyto-destructive therapies etc Role for Intra-lesional therapies eg TVEC
Possible Treatment Algorithm High Risk for Further LNF relapse (No Systemic Adjuvant options) Observation Consider RT IF Very High Risk of LNF relapse Extensive ECE, heavy tumor burden (NB distant relapse!) BUT!! Consider BMI, QOL THEN Consider RT for Relapse in a location difficult to salvage Pt who will never get systemic therapy Salvage - Systemic therapy - Surgery / RT Adjuvant Systemic Therapy Interferon NO Clinical Trials
Time to Late Surgical Toxicity Subcutaneous Tissue Morbidity Grade 2 + HR = 2.25 p < 0.001 Pain, Nerve, Joint, Other No difference